Genome Sequence Marks Big Leap Forward for Frog Researchers

An African clawed frog has joined the spotted green puffer fish, the honeybee, and the human among the ranks of more than 175 organisms that have had their genetic information nearly completely sequenced.

While the research could help scientists better understand the factors causing the vast die-off of amphibians around the globe, scientists are also excited about the potential the finding has to improve human health by giving scientists a new tool to understand how our genes work at the most basic level.

The genome – the collection of genetic information – of Xenopus tropicalis, a native of sub-Sahara Africa that lives nearly entirely in water, is published in a paper in the April 30 issue of the journal Science. Authors include Jacques Robert, Ph.D., an immunologist at the University of Rochester Medical Center, one of two dozen institutions worldwide that cooperated in the study. The overall effort was led by Uffe Hellsten of the U.S. Department of Energy Joint Genome Institute in Walnut Creek, Calif.

Xenopus tropicalis

The Xenopus tropicalis genome is composed of more than 1.7 billion chemical bases spread out on 10 chromosomes. The team found that its genome has between 20,000 and 21,000 genes, including more than 1,700 genes that are very similar to genes in people that are related to conditions like cancer, asthma, and heart disease.

Robert’s group contributed significantly to information on about 200 of the frog’s genes.

“This is a great starting point for really working with Xenopus to understand how genes are regulated,” said Robert, associate professor of Microbiology and Immunology. “It’s a big step forward. Now the real work begins – understanding how and when those genes are turned on or off, and how they work together during development and disease. Xenopus holds the promise of becoming a very powerful model to help us learn more about our own genes.”

Robert noted that cracking the genome code is a far cry from actually understanding how genes work. In humans, for instance, the genetic code was published in 2001, but the science of understanding how our genes actually work is still in its infancy.

“Having the genome in hand helps make Xenopus very attractive for the further study of gene organization, regulation and function,” Robert added.

The findings published in Science are based on the DNA of a single African clawed frog whose DNA was broken down into small pieces that were replicated many, many times, then sent to laboratories around the world for analysis. The project sprang from a meeting of researchers in Walnut Creek, Calif., in 2002, when the world’s top Xenopus experts, including Robert, decided to join forces to conquer the genome of Xenopus tropicalis, a common research subject for genetics researchers.

Xenopus tropicalis becomes the first frog to join the list of organisms whose genomes have been sequenced by scientists. In addition to the spotted green puffer fish, the honeybee, and the human, the list includes dozens of pathogens that infect people, as well as at least one species each of mosquito, fruit fly, flower, worm, dog, rat and chicken.

Frogs and humans share many features in the earliest stages of their development, dating back to a time before they went their separate ways 360 million years ago. Many of a frog’s systems, such as its nervous, skeletal and immune systems, develop much like a person’s do, and so frogs are frequently used by scientists trying to understand people at their most basic level.

For instance, the 1,700 genes in Xenopus tropicalis that are very similar to disease-related genes in people give scientists a laboratory of sorts to analyze those genes, to learn how they cause disease in people.

Scientists found additional similarities between the frog genes and human genes. For instance, genes in frogs have very similar neighboring genes as humans about 90 percent of the time. In other words, the frog genome contains the same sort of “gene neighborhoods” as the human genome. This is important as scientists try to understand how groups of neighboring genes work together. Such questions are significant, as many conditions, such as heart disease and cancer, are thought to be related to activity by scores, if not hundreds, of genes, as well as lifestyle and other environmental factors.

A surprise finding is the number of mobile genetic elements, sometimes called “jumping genes,” that scientists found in the Xenopus genome. Such sequences, known as transposons, were once considered “junk DNA” simply because scientists did not know if they had a function, but now, many scientists believe they may be key in determining how an organism’s genes actually work.

One-third of the frog genome is made up of transposons, and of those, an unusually high percentage – three-quarters – of the transposons are DNA transposons, capable of moving genes around directly. Scientists are trying to understand the implications.

Among the worldwide team, Robert is one of two authors who specialize in the immune system – understanding how the body protects itself from threats like microbes and other foreign invaders, and how the body understands what to attack and what not to attack. Confusion on that front leads to disorders that afflict hundreds of millions of people with conditions like asthma, lupus, multiple sclerosis, and rheumatoid arthritis.

A better understanding of the immune system is also important for more effectively treating diseases like cancer or Alzheimer’s disease. Scientists, including several at the University of Rochester Medical Center, are trying to develop vaccines that are specially designed to fight these diseases by incorporating information about how the immune system separates friend from foe. Frogs develop such a system not just once, like most organisms, but twice – the second time when they remake themselves and morph from tadpole to frog.

In the current study, Robert and colleagues found a striking similarity between frogs and humans among genes related to proteins known as MHC (major histocompatibility complex) proteins, which play a key role helping an organism detect foreign materials or organisms, as well as in detecting and controlling cancerous cells.

In addition to his work decoding Xenopus tropicalis, Robert heads a unique international resource in Rochester: the Xenopus laevis Research Resource for Immunobiology. The laboratory, funded by the National Institute of Allergy and Infectious Diseases, does extensive work on a species of frog that is a bigger cousin to the one discussed in the Science paper. It’s the world's most comprehensive resource specializing in the use of Xenopus for immunological research.

The resource has been funded by NIAID since 2004 and was recently funded for another five years. Through the laboratory, which is devoted to research in immunology and biomedical research, Robert and colleagues make available to other scientists around the globe tools such as reagents, antibodies, and genetically modified frogs for study.